Abstract/Summary Commensal oral streptococci are the most abundant bacteria in the biofilms that colonize the hard and soft tissues of the human oral cavity and many areas of the nasopharynx. These health-associated bacteria employ multiple diverse adhesion strategies and produce a spectrum of compounds and macromolecules that inhibit the colonization and virulence of pathogens. With support from R01 DE25832, a large collection of commensal oral streptococci has been isolated from healthy subjects, then characterized at the phenotypic and genomic levels for properties that may promote oral and systemic health. Here, we propose to screen these highly diverse strains for their ability to bind to and degrade purified SARS-CoV-2 surface proteins and to interfere with CoV-2 Spike protein engagement of the viral receptor, ACE2. Standard methods will then be used to identify the streptococcal gene products that mediate inhibitory activities. Defined mutants and overexpressing strains will be utilized to confirm the results. Though not a focus of this Urgent Revision application, it is noteworthy that, as part of DE25832, we have developed a mouse model in which we can establish various commensal streptococci in the oral cavity, then challenge the commensal-colonized mice with a pathogen(s). Such a model could be adapted to in vivo animal challenge studies. Importantly, novel systems for formulation and delivery of one of our commensal strains have already been optimized through an international collaboration, and thus we are well positioned to rapidly translate our in vitro findings to clinical trials of a therapeutic probiotic intervention.